title: In vitro evaluation of the safe margin, antithrombotic and antiproliferative actions for the treatment of restenosis: Nitric oxide donor and polymers.
abstract: Drug-eluting stents (DES) were developed to combat the problem of in-stent restenosis, and evaluating the biological activity from DES systems is critical for its safety and efficacy. To test the cytotoxicity of nitric oxide (NO) donor-containing polymers for their potential use in DES applications, S-nitrosoglutathione (GSNO) or in combination with poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) in an aqueous polymeric solution (PVA/PVP/GSNO) was investigated using Balb/c 3T3 and Rabbit arterial smooth muscle (RASM) cells. The sensitivity of 3T3 cells to the cytotoxicity effects induced by GSNO was higher than that of RASM cells, while RASM cells were more susceptible to alterations in membrane permeability. Cell growth assays showed that GSNO and PVA/PVP/GSNO induced antiproliferative effects in RASM cells. Moreover, the presence of polymers can reduce the cytotoxicity and enhance the antiproliferative effects of GSNO. Dose-dependent inhibition of platelet aggregation was similar for both PVA/PVP/GSNO (EC50 of 3.4 ± 2.3 µM) and GSNO (EC50 of 2.8 ± 1.1 µM) solutions. Platelet adhesion assays showed that the inhibition caused by GSNO (EC50 of 5.0 mM) was dependent on the presence of plasma. These results demonstrate that the methodology adopted here is suitable to establish safety margins and evaluate the antithrombotic potential and antiproliferative effects of NO-eluting biomaterials and polymeric solutions for the new cardiovascular devices, and also to emphasize the importance of using more specific cell lines in these evaluations.
authors.affiliation: Laboratory of Cardiovascula, Department of Anatomy, Cellular Biology and Physiology, State University of Campinas, Biology Institute, SP, Brasil.
authors.forename: Cláudia de Lourdes
authors.initials: Cde L
authors.lastname: Sorragi
authors.forename: Silvia Mika
authors.initials: SM
authors.lastname: Shishido
authors.forename: Maria Edwiges
authors.initials: ME
authors.lastname: Lemos
authors.forename: Sissi
authors.initials: S
authors.lastname: Marcondes
authors.forename: Edson
authors.initials: E
authors.lastname: Antunes
authors.forename: Marta H
authors.initials: MH
authors.lastname: Krieger
mesh_terms: D000818:Animals; D041702:BALB 3T3 Cells; D049109:Cell Proliferation / Q000187:drug effects; D023903:Coronary Restenosis / Q000188:drug therapy / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D054855:Drug-Eluting Stents; D064420:Drug-Related Side Effects and Adverse Reactions / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D032389:Myocytes, Smooth Muscle; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011142:Polyvinyl Alcohol / Q000494:pharmacology; D011205:Povidone / Q000494:pharmacology; D011817:Rabbits; D026422:S-Nitrosoglutathione / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D005343:Fibrinolytic Agents; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D011142:Polyvinyl Alcohol; D011205:Povidone